Huntington's Disease (HD) and Alzheimer's disease (AD) are neurodegenerative disorders characterized by the accumulation of misfolded proteins. Sadly, many years of research into the mechanisms of neurodegeneration have failed to produce effective therapies that halt or reverse these diseases. We recently completed a genomic screen in S. cerevisiae with single gene deletion strains that identified kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway (KP) of tryptophan degradation, as a potent suppressor of mutant huntingtin (htt) toxicity. The brain levels of two neurotoxic metabolites in the KP, quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK), are increased in the striatum and neocortex in early grade HD; similar increases in QUIN and/or 3-HK are present in three mouse models of HD. We show that brain levels of QUIN are increased in the hippocampus and entorhinal cortex of mouse models of AD, but not in the striatum or other unaffected brain regions. QUIN and 3-HK have long been hypothetically linked to the pathophysiology of neurological diseases including HD and AD. Indeed, intrastriatal injection of QUIN together with 3-HK causes striatal lesions resembling those found in HD that may be mediated by the combination of A/-methyl D-aspartate (NMDA) receptor over-stimulation (excitotoxicity) and free radical formation. Subchronic intraventricular infusion of QUIN in rats produces biochemical changes and memory deficits that may share similarities with those found in AD patients. In our proposal, we present data showing that treatment of a mouse model of HD with Ro 61-8048, a high-affinity, orally bioavailable, small-molecule inhibitor of KMO, improved multiple behavioral outcome measures despite the fact that this compound displayed marginal penetration across the blood brain barrier (BBB). We recently generated a novel series of brain penetrating KMO inhibitors and mice that carry a conditional null allele of Kmo. With these tools in hand, we are for the first time in a position to test rigorously if the microglial KP and excitotoxicity play important roles in mouse models of HD and AD. The following specific aims will begin to test the hypothesis that microglial derived increases in neurotoxic KP metabolites occur in distinct brain microenvironments in a manner that contributes to selective neuronal vulnerability in mouse models of HD and AD: AIM 1. To determine if genetic and pharmacological inhibition of KMO in microglia improves behavioral and pathological outcome measures in mouse models of HD and AD; AIM 2. To identify the regulatory elements and signal transduction pathways that mediate mutant huntingtin (htt)/amyloid (3-protein (A|3)-induced KP activation in microglia; AIM 3. To determine the cellular mechanisms that mediate increases in toxic microglial KP metabolites in discrete brain microenvironments in a mouse model of HD. In summary, these experiments will determine if pharmacological inhibition of KMO may be a bona fide therapeutic approach to treating HD and AD.